Human islet-derived, islet-reactive T cells from subjects with Type 1 diabetes

来自 1 型糖尿病患者的人胰岛衍生的胰岛反应性 T 细胞

基本信息

批准号：
9280795
负责人：
SALLY Choate KENT
金额：
$ 20.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280795
关键词：
Activities of Daily Living Antigen-Presenting Cells Autoantigens Autoimmune Process Autoimmune Responses B-Lymphocytes Biological Assay Blocking Antibodies CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Line Cell surface Cells Childhood Cities Clinical Trials Clone Cells Coupled Diabetes Mellitus Disease Engineering Epitopes Future Goals Histology Human Immunohistochemistry Immunotherapy In Situ Inbred NOD Mice Individual Infiltration Innate Immune System Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Left Lymphocytic Infiltrate Massachusetts Methods Modeling Modification Organ Donor Pancreas Pathogenesis Peptides Peripheral Phenotype Post-Translational Protein Processing Prevention Proinsulin Proteins Reagent Receptor Cell Recovery Regulatory T-Lymphocyte Reporting Research Design Research Personnel Risk Rodent Model Sampling T-Cell Receptor T-Lymphocyte Translating Translations United States Universities Ursidae Family autoreactive T cell autoreactivity cell type cytokine cytotoxicity design disorder risk human disease human subject humanized mouse immunopathology insight islet lymph nodes medical schools mouse model peripheral blood programs success tool

项目摘要

PROJECT SUMMARY/ABSTRACT Understanding the autoimmune response in human type 1 diabetes (T1D) is crucial for the design of successful immunotherapies for those at-risk for the disease as well as for those with established disease. While studies of rodent models of have greatly instructed us on the autoimmune process, the translation of successful therapies and prevention studies in the rodent models to human clinical trials has been far less successful. While we know much information concerning islet infiltrating T cells in the rodent models and islet infiltrates in humans with T1D by histology and immunohistochemistry, we previously have not had the opportunity to isolate directly the lymphocytic infiltrate from human with T1D for repertoire analysis and functional capacity. We have received islet isolations from 7 individuals with T1D and have grown or sorted directly out of the islets, 95 CD4 and CD* T cell lines. We have demonstrated the reactivity and HLA restriction of 4 CD4+ T cell lines and 3 CD8+ T cells lines (multiple reactivities are represented). The purpose of this proposal is to assay each T cell line for reactivity to whole normal islets, whole islet proteins, known islet- associated peptide targets of autoreactive T cells, to peptides derived from islet proteins that bear post- translational modifications, to define their HLA restriction, and define their effector functions. These islet- infiltrating T cells will be vital tools/reagents for investigators in the field to study the function of islet-infiltrating T cells in humanized mouse models of T1D, T cell receptor repertoire, to preserve autoreactive T cell receptors for future studies, in functional assays of autoreactive T cell interactions with T regulatory cells, B cell, antigen presenting cells and the innate immune system. Finally, these studies will inform investigators in the design of successful immunotherapies for those at-risk for T1D and especially for those with established T1D.

项目概要/摘要了解人类 1 型糖尿病 (T1D) 的自身免疫反应对于设计为那些有患病风险以及已确诊疾病的人提供成功的免疫疗法。虽然对啮齿动物模型的研究极大地指导了我们自身免疫过程，但从啮齿动物模型到人体临床试验的成功治疗和预防研究要少得多成功的。虽然我们知道很多有关啮齿动物模型和胰岛中胰岛浸润 T 细胞的信息通过组织学和免疫组织化学，我们以前没有发现过 T1D 患者的浸润情况有机会直接从 T1D 患者中分离淋巴细胞浸润以进行谱分析功能能力。我们已收到 7 名 T1D 患者的胰岛分离物，并进行了培养或分类直接从胰岛中提取 95 个 CD4 和 CD* T 细胞系。我们已经证明了反应性和 HLA 限制 4 个 CD4+ T 细胞系和 3 个 CD8+ T 细胞系（表示多种反应性）。这样做的目的建议检测每个 T 细胞系对整个正常胰岛、整个胰岛蛋白、已知胰岛的反应性自身反应性 T 细胞的相关肽靶标，以及源自胰岛蛋白的肽，这些肽具有后翻译修饰，以定义其 HLA 限制，并定义其效应器功能。这些小岛—— 浸润性T细胞将成为该领域研究人员研究胰岛浸润功能的重要工具/试剂 T1D 人源化小鼠模型中的 T 细胞、T 细胞受体库，以保留自身反应性 T 细胞受体用于未来研究，用于自身反应性 T 细胞与 T 调节细胞、B 细胞、抗原相互作用的功能测定呈现细胞和先天免疫系统。最后，这些研究将为研究人员设计为那些有 T1D 风险的人，特别是那些已经确诊的 T1D 患者提供成功的免疫疗法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Corrigendum: Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

勘误表：1 型糖尿病人类捐献者胰岛浸润 T 细胞自身抗原特异性的分析。

DOI：
10.1038/nm0817-1004a
发表时间：
2017
期刊：
Nature medicine
影响因子：
82.9
作者：
Babon,JennyAurielleB;DeNicola,MeganE;Blodgett,DavidM;Crèvecoeur,Inne;Buttrick,ThomasS;Maehr,René;Bottino,Rita;Naji,Ali;Kaddis,John;Elyaman,Wassim;James,EddieA;Haliyur,Rachana;Brissova,Marcela;Overbergh,Lut;Mathieu,Chanta
通讯作者：
Mathieu,Chanta